The overall goal of this proposal is to clarify the role of cytokines in antigen-driven naive CD4+ T cell activation in vivo. Despite the well established role of IL-2 in the priming of naive T cell proliferation in vitro, growing evidence suggests that in vivo, IL-2 is not required for this process. Our hypothesis is that optimal antigen-driven proliferation of naive CD4+ T cells is promoted redundantly in vivo by StatS signals activated by gamma common-dependent cytokines, and Stat5 signals activated by gp130-dependent cytokines. Using an in vivo experimental system that enables genetic manipulation of naive CD4+ T cells just prior to antigen stimulation, the signaling functions of these candidate cytokines will be blocked to assess their role in promoting proliferation and development into Th effector cells. This strategy will avoid complications arising from the pleiotropic roles of these cytokines in other stages of T cell development, which have undermined interpretations of past in vivo studies. [unreadable] [unreadable]